Duchenne Muscular Dystrophy (DMD) affects 1:5,000 male births (20,000 new cases in the USA each year) making it the most common fatal genetic disorder. The need for lifelong clinical care and the high morbidity are also associated with total costs that exceeded $750 million in the United States in 2010. DMD is caused by a variety of point mutations in the X-linked dystrophin gene all of which lead to a lack of functiona dystrophin that links actin to the sarcolemma in both cardiac and skeletal muscle. Without a functional dystrophin complex, repetitive mechanical stress leads to cardiomyocyte death, then fibro-fatty replacement that elevates the risk of a fatal arrhythmia and foments cardiomyopathy. The appearance of cardiac involvement at the earliest time point likely reflects a shift in the balance between the reparative capabilities of normal development and the crippling effects of DMD. Initiating drug therapy before the balance tips is likely the key to optimal clinical therapy, but identifying this time point remains elusive. Initiating drug therapy at an early pre-symptomatic age is ill-advised because of potential side effects, but waiting for overt phenotypes leads to sub-optimal clinical care and a missed opportunity to potentially slow disease progression. One objective of this project is to define the precision and reproducibility of several diagnostic cardiac MRI biomarkers obtained during a fast, free-breathing cardiac MRI exam. This will enable the team to bridge the significant multi-year diagnostic gap between early genotyping and the late onset of overt cardiac symptoms. A second objective is to define the cardiac-specific genotype-phenotype correlation via outlier analysis. The specific aims are: SPECIFIC AIM-1 - Characterize fast, free-breathing MRI biomarkers of myocardial tissue- composition and regional cardiac function in boys with DMD. The objective is to evaluate the precision and reproducibility of several quantitative MRI biomarkers and compare them to measures of focal fibrosis (late gadolinium enhancement) - the current gold standard biomarker for cardiac involvement in DMD. The team will also compare several regional cardiac function biomarkers to cardiac grid-tag derived circumferential strain using conventional breath holding. SPECIFIC AIM-2 - Assess the prognostic value of our cardiac MRI biomarkers for worsening global LV function. The objective is to define the most sensitive cardiac MRI biomarkers of tissue-composition and regional cardiac function that portend the onset of overt changes in cardiac strain and ejection fraction, a late clinical outcome in boys with DMD. SPECIFIC AIM-3 - Propose mechanisms of cardiac dysfunction or protective phenotypes using genomic analysis. The objective is to identify specific genetic determinants that are associated with outlier (unusually mild or severe) phenotypes and evaluate the functional cardiac biomarker correlates. Public Health Significance - The results of this work will enable clinicians managing the care of boys with DMD to initiate drug therapy at a time when the progression may be slowed, but late enough to mitigate potential side effects, thus making treatment more effective for boys with DMD as well as improving quality of life.